Abstract: Our overall goal is to develop new clinical approaches to restore upper-limb function after incomplete cervical spinal cord injury (SCI). Corticospinal tract (CST) axons are involved in controlling upper-limb function. Paired-pulse induced spike-timing dependent plasticity (STDP) enhances synaptic strength between residual CST axons and spinal motoneurons (SMNs) resulting in temporary improvements in upper-limb function in humans with incomplete cervical SCI. Our specific goals are to: 1) develop methodologies to maximize STDP-induced aftereffects in an adult rat model of incomplete SCI and 2) translate this knowledge to humans to maximize STDP-mediated motor function recovery after incomplete cervical SCI. STDP aftereffects depend on the parameters of stimulation and the activation of postsynaptic glutamate NMDA and AMPA receptors causing increased synaptic transmission. In Aim 1, we will use an adult rat model of incomplete cervical SCI to examine the effects of increasing paired-pulse frequencies and duration, and extended use of clinically-relevant NMDA and AMPA receptor agonists on the strength of electrophysiological and forelimb functional STDP aftereffects. Motor training will be combined with paired-pulse STDP stimulation to further enhance plasticity and behavioral recovery. Comprehensive assessment of cellular and molecular plasticity in the brain and spinal cord will be used to study neuronal mechanisms underlying the effects of our approaches. In Aim 2, we will translate the knowledge from Aim 1 to humans with incomplete cervical SCI. The most effective stimulation parameters and pharmacological agent will be used in humans during functionally relevant reach to grasp motor tasks. Motor training of reach and grasp movements will be combined with STDP-paradigms to further enhance behaviorally relevant plasticity and recovery of function. Our experiments will provide new knowledge on STDP-mediated aftereffect mechanisms in an adult rat model of incomplete cervical SCI (Aim 1) which will be used to maximize STDP aftereffects in humans with incomplete cervical SCI (Aim 2). The results may support the development of more effective clinically-relevant STDP protocols to improve daily use of upper-limb function in humans with SCI. The relevance of this proposal is highlighted by the restricted efficacy of current strategies to improve hand function after SCI.